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Background Chorioamnionitis is associated with increased rates of bronchopulmonary dysplasia (BPD) in ventilated preterm infants. Budesonide when added to surfactant decreased lung and systemic inflammation from mechanical ventilation in preterm lambs and decreased the rates and severity of BPD in preterm infants. We hypothesized that the addition of budesonide to surfactant will decrease the injury from mechanical ventilation in preterm lambs exposed to intra-amniotic (IA) lipopolysaccharide (LPS). Methods Lambs at 126 ± 1 day GA received LPS 10 mg IA 48 h prior to injurious mechanical ventilation. After 15 min, lambs received either surfactant mixed with: (1) saline or (2) Budesonide 0.25 mg/kg, then ventilated with normal tidal volumes for 4 h. Injury markers in the lung, liver, and brain were compared. Results Compared with surfactant alone, the addition of budesonide improved blood pressures, dynamic compliance, and ventilation, while decreasing mRNA for pro-inflammatory cytokines in the lung, liver, and multiple areas of the brain. LPS caused neuronal activation and structural changes in the brain that were not altered by budesonide. Budesonide was not retained within the lung beyond 4 h. Conclusions In preterm lambs exposed to IA LPS, the addition of budesonide to surfactant improved physiology and markers of lung and systemic inflammation. Impact The addition of budesonide to surfactant decreases the lung and systemic responses to injurious mechanical ventilation preterm lambs exposed to fetal LPS. Budesonide was present in the plasma by 15 min and the majority of the budesonide is no longer in the lung at 4 h of ventilation. IA LPS and mechanical ventilation caused structural changes in the brain that were not altered by short-term exposure to budesonide. The budesonide dose of 0.25 mg/kg being used clinically seems likely to decrease lung inflammation in preterm infants with chorioamnionitis.

The Gram-negative bacterium Klebsiella pneumoniae is a frequent pathogen causing outbreaks in neonatal intensive care units. Some Enterobacteriaceae can acquire the ability to sequester iron from infected tissue by secretion of iron-chelating compounds such as yersiniabactin. Here we describe an outbreak and clinical management of infections because of a highly virulent yersiniabactin-producing, nonmultiresistant K. pneumoniae strain in a neonatal intensive care unit. Outbreak investigation and effectiveness assessment of multidisciplinary infection control measurements to prevent patient-to-patient transmission of highly pathogenic K. pneumoniae were undertaken.Outbreak cases were identified by isolation of K. pneumoniae from blood or stool of infants. Clinical data were abstracted from medical charts. K. pneumoniae isolates were genotyped using whole genome sequencing, and yersiniabactin production was evaluated by luciferase assay.Fourteen cases were confirmed with 8 symptomatic and 6 colonized patients. Symptomatic patients were infants of extremely low gestational and chronologic age with fulminant clinical courses including necrotizing enterocolitis and sepsis. Whole genome sequencing for bacterial isolates confirmed the presence of an outbreak. All outbreak isolates produced yersiniabactin.Yersiniabactin-producing K. pneumoniae can display a high pathogenicity in extremely premature infants with low chronologic age. This outbreak also underlines the considerable potential of today's infection control systems for recognizing and controlling nosocomial infections in highly vulnerable populations.

Neonatal sepsis is a major cause of morbidity and mortality in very low birth weight infants (VLBWI). Nurse workload considerably affects infection rates in intensive care units. However, data concerning the impact of staff workload on bloodstream infections (BSI) in VLBWI are scarce. The aim of the study was to examine the association between nurse workload and BSI in VLBWI. VLBWI admitted to our neonatal intensive care unit during 2016–2017 were retrospectively analysed. Association between nurse workload, determined by a standardized nursing score, and the BSI occurrence was investigated. A higher nurse workload was significantly associated with higher occurrence of BSI (p = 0.0139) in VLBWI. An assumed workload of 120% or higher, representing the need for additional nurses in our NICU setting, is associated with an elevated risk for BSI in this vulnerable population OR 2.32 (95% CI: 1.42–3.8, p = 0.0005). In conclusion, nurse understaffing is associated with a higher risk for BSI in VLBWI.

The Gram-negative bacterium Klebsiella pneumoniae is a frequent pathogen causing outbreaks in neonatal intensive care units. Some Enterobacteriaceae can acquire the ability to sequester iron from infected tissue by secretion of iron-chelating compounds such as yersiniabactin. Here we describe an outbreak and clinical management of infections because of a highly virulent yersiniabactin-producing, nonmultiresistant K. pneumoniae strain in a neonatal intensive care unit. Outbreak investigation and effectiveness assessment of multidisciplinary infection control measurements to prevent patient-to-patient transmission of highly pathogenic K. pneumoniae were undertaken.

Background: While there is a proven association of upper genital tract Ureaplasma infection during pregnancy with adverse pregnancy outcome, the effect of vaginal Ureaplasma colonization on preterm delivery has been controversially debated. Objectives: We hypothesized that women with isolation of vaginal U. parvum but not U. urealyticum are at increased risk for spontaneous preterm birth (SPB) compared to women with negative results. Methods: A vaginal swab taken between 12 and 14 weeks of gestation was analyzed for the presence of Ureaplasma biovars by PCR in 4,330 pregnant women. Results: Of the study cohort, 37% were positive for U. parvum, 5.9% for U. urealyticum, and 3.1% for both. The rates of SPB were 10.4% (OR 1.7, 95% CI 1.3, 2.2, p < 0.001) and 8.9% (OR 1.4, 95% CI 0.9, 2.3, p = 0.193) in the groups with isolation of U. parvum and U. urealyticum, respectively, compared to 6.4% in the group with negative PCR results. Multiple logistic regression and interaction analyses showed that vaginal colonization with U. parvum but not U. urealyticum was a statistically significant risk factor for SPB (adjusted OR 1.6, 95% CI 1.2, 2.1, p < 0.001), independent of other risk factors such as bacterial vaginosis and history of SPB. Conclusion: Our study demonstrates a statistically significant and independent association between first-trimester vaginal colonization with U. parvum and subsequent SPB.

Background: Methicillin-susceptible Staphylococcus aureus (MSSA) is a major contributor to infectious episodes of very low birth weight infants (VLBWI), resulting in significant morbidity and mortality. Objective: To examine the efficacy and safety of surveillance cultures and the decolonization of MSSA-colonized VLBWI. Methods: VLBWI admitted to our neonatal wards in 2011-2016 were retrospectively analyzed. Rates of MSSA-attributable infections were compared before and after the implementation of active surveillance cultures and the decolonization of MSSA-colonized patients. The mupirocin susceptibility of isolated MSSA strains was routinely tested. Results: A total of 1,056 VLBWI were included in the study, 552 in the pre-intervention period and 504 in the post-intervention period. The implementation of surveillance cultures and decolonization of colonized patients resulted in a 50% reduction of incidence rates per 1,000 patient-days of MSSA-attributable infections (1.63 [95% CI 1.12-2.31] vs. 0.83 [95% CI 0.47-1.35], p = 0.024). No adverse effects were observed from application of the decolonization protocol with mupirocin and octenidin. No mupirocin-resistant MSSA strains were detected during the study period. Conclusion: Implementation of an active surveillance and decolonization protocol resulted in a reduction of MSSA-attributable infections in VLBWI.

Background Healthcare-associated infections represent a major burden in neonatal intensive care units. Hand antisepsis is the most important tool for prevention, however, compliance among healthcare workers remains low. Objectives To prospectively evaluate the influence of different work shifts (extended working hours, night shifts) on the quality of healthcare workers’ hand antisepsis. Design Observational study. Settings Two equivalent “Level III” neonatal intensive care units at the University Hospital Vienna, Austria. Participants Seventy healthcare workers, 46 nurses and 24 physicians. Methods The Semmelweis Scanner, an innovative training device assessing the quality of hand antisepsis with an ultraviolet dye labelled alcohol-based hand rub, was employed to collect data on the hand surface coverage achieved during hand antisepsis of participants. It provides visual feedback of appropriately versus inappropriately disinfected areas of the hand and can also be used for the objective quantification of hand surface coverage with the hand rub. Measurements were performed before and after 12.5 hour (h) day and night shifts (nurses), as well as before and after regular 8h day shifts and extended 25h shifts (physicians). To avoid any bias caused by residual ultraviolet marker, scans had to be separated by 24 hours periods. Primary outcome was the hand surface coverage with the hand rub: Hand scans were categorized as “passed” if an appropriate quality of hand hygiene, defined as a minimum 97% coverage of hand surface, was achieved. A generalized mixed model was used to analyse the data accounting for repeated measurements. Results Seventy healthcare workers performed a total of 485 scans. Sixteen scans had to be excluded, resulting in 466 scans for further analyses. A difference in the predicted probability of achieving appropriate hand antisepsis was found between the beginning and end of extended shifts: In physicians, adequate hand antisepsis was remarkably reduced after 25h shifts (predicted probability 99.4% vs 78.8%), whereas there was no relevant difference between the beginning and end of 8h day shifts (92.2% vs 97.3%). In nurses, a relevant difference was found between the beginning and end of 12.5h day shifts (88.6% vs 73.6%). This difference was not found for 12.5h night shifts. The most frequently missed area on the hands was the right dorsum. Conclusion The quality of hand antisepsis of healthcare workers in neonatal intensive care units may be associated with long working hours.

Ureaplasma species (spp) are the bacteria most often isolated from the amniotic cavity of women with preterm labor or preterm premature rupture of membranes; thus, the link between intrauterine Ureaplasma spp infection and adverse pregnancy outcome clearly is established. However, because vaginal Ureaplasma spp colonization is very common in pregnant women, the reason that these microorganisms cause ascending infections in some cases but remain asymptomatic in most pregnancies is not clear. Previous studies suggested an association between vaginal colonization with Ureaplasma parvum as opposed to U urealyticum and preterm delivery. However, because of the high frequency of vaginal Ureaplasma spp colonization during pregnancy, additional risk factors are needed to select a group of women who might benefit from treatment.To further identify pregnant women who are at increased risk for preterm delivery, the aim of the present study was to investigate U parvum serovar-specific pathogenicity in a large clinical cohort.We serotyped 1316 samples that were positive for U parvum using a high-resolution melt polymerase chain reaction assay, and results were correlated with pregnancy outcome.Within U parvum positive samples, serovar 3 was the most common isolate (43.3%), followed by serovar 6 (31.4%) and serovar 1 (25.2%). There was a significantly increased risk for spontaneous preterm birth at very low (32 weeks gestation; P.005) and extremely low (28 weeks gestation; P.005) gestational age in the group with vaginal U parvum serovar 3 colonization compared with the control group of pregnant women who tested negative for vaginal Ureaplasma spp colonization. This association was found for neither serovar 1 nor serovar 6. The combination of vaginal U parvum serovar 3 colonization and diagnosis of bacterial vaginosis in early pregnancy or a history of preterm birth further increased the risk for adverse pregnancy outcome.Colonization with U parvum serovar 3, but not serovar 1 or serovar 6, in early pregnancy is associated with preterm delivery at very and extremely low gestational age. The combination of U parvum serovar 3 colonization and a history of preterm birth or bacterial vaginosis further increases the risk for spontaneous preterm birth at low gestational age and may define a target group for therapeutic intervention studies.

Nasal cultures are commonly used to detect carriers of Staphylococcus aureus (SA) in infants. Combination of nasal and skin swabs has been shown to enhance the detection rate of SA colonization in adult hospitalized patients. Combining nasal swabs with expanded body skin swabs enhanced detection of SA colonization in premature infants in a tertiary care neonatal department.

Background: Antenatal corticosteroids (ACS) improve preterm neonatal outcomes. However, uncertainty remains regarding the safety of ACS exposure for the developing fetus, particularly its neurosensory development. Objectives: We investigated the effect of single and multiple ACS exposures on auditory nerve development in an ovine model of pregnancy. Methods: Ewes with a single fetus (gestational age [GA] 100 days) received an intramuscular injection of 150 mg medroxyprogesterone-acetate, followed by intramuscular (i) betamethasone (0.5 mg/kg) on days 104, 111, and 118 GA; (ii) betamethasone on day 104 and saline on days 111 and 118 GA; or (iii) saline on days 104, 111, and 118 GA, with delivery on day 125 GA. Transmission electron microscope images of lamb auditory nerve preparations were digitally analyzed to determine auditory nerve morphology and myelination. Results: Relative to the control, mean auditory nerve myelin area was significantly increased in the multiple-treatment group (p < 0.001), but not in the single-treatment group. Increased myelin thickness was significantly changed only in a subgroup analysis for those axons with myelin thickness greater than the median value (p < 0.001). Morphological assessments showed that the increased myelin area was due to an increased likelihood of decompacted areas (p = 0.005; OR = 2.14, 95% CI 1.26–3.63; 31.6 vs. 18.2% in controls) and irregular myelin deposition (p = 0.001; OR = 5.91, 95% CI 2.16–16.19; 49.0 vs. 16.8% in controls) in the myelin sheath. Conclusions: In preterm sheep, ACS exposure increased auditory nerve myelin area, potentially due to disruption of normal myelin deposition.

Introduction Diagnosis of neonatal sepsis remains a major challenge in neonatology. Most molecular-based methods are not customized for neonatal requirements. The aim of the present study was to assess the diagnostic accuracy of a modified multiplex PCR protocol for the detection of neonatal sepsis using small blood volumes. Methods 212 episodes of suspected neonatal late onset sepsis were analyzed prospectively using the Roche SeptiFast® MGRADE PCR with a modified DNA extraction protocol and software-handling tool. Results were compared to blood culture, laboratory biomarkers and clinical signs of sepsis. Results Of 212 episodes, 85 (40.1%) were categorized as "not infected". Among these episodes, 1 was false positive by blood culture (1.2%) and 23 were false positive by PCR (27.1%). Of 51 (24.1%) episodes diagnosed as "culture proven sepsis", the same pathogen was detected by blood culture and PCR in 39 episodes (76.5%). In 8 episodes, more pathogens were detected by PCR compared to blood culture, and in 4 episodes the pathogen detected by blood culture was not found by PCR. One of these episodes was caused by Bacillus cereus, a pathogen not included in the PCR panel. In 76/212 (35.8%) episodes, clinical sepsis was diagnosed. Among these, PCR yielded positive results in 39.5% of episodes (30/76 episodes). For culture-positive sepsis, PCR showed a sensitivity of 90.2% (95%CI 86.2-94.2%) and a specificity of 72.9% (95%CI 67.0-79.0%). Conclusion The Roche SeptiFast® MGRADE PCR using a modified DNA extraction protocol showed acceptable results for rapid detection of neonatal sepsis in addition to conventional blood culture. The benefit of rapid pathogen detection has to be balanced against the considerable risk of contamination, loss of information on antibiotic sensitivity pattern and increased costs.

Methicillin-susceptible Staphylococcus aureus (MSSA) is a major contributor to infectious episodes of very low birth weight infants (VLBWI), resulting in significant morbidity and mortality.To examine the efficacy and safety of surveillance cultures and the decolonization of MSSA-colonized VLBWI.VLBWI admitted to our neonatal wards in 2011-2016 were retrospectively analyzed. Rates of MSSA-attributable infections were compared before and after the implementation of active surveillance cultures and the decolonization of MSSA-colonized patients. The mupirocin susceptibility of isolated MSSA strains was routinely tested.A total of 1,056 VLBWI were included in the study, 552 in the pre-intervention period and 504 in the post-intervention period. The implementation of surveillance cultures and decolonization of colonized patients resulted in a 50% reduction of incidence rates per 1,000 patient-days of MSSA-attributable infections (1.63 [95% CI 1.12-2.31] vs. 0.83 [95% CI 0.47-1.35], p = 0.024). No adverse effects were observed from application of the decolonization protocol with mupirocin and octenidin. No mupirocin-resistant MSSA strains were detected during the study period.Implementation of an active surveillance and decolonization protocol resulted in a reduction of MSSA-attributable infections in VLBWI.

Extremely preterm infants born at the border of viability (22-24 weeks' gestation) have high rates of death and lasting disability. Ex vivo uterine environment therapy is an experimental neonatal intensive care strategy that provides gas exchange using parallel membranous oxygenators connected to the umbilical vessels, sparing the extremely preterm cardiopulmonary system from ventilation-derived injury.In this study, we aimed to refine our ex vivo uterine environment therapy platform to eliminate fetal infection and inflammation, while simultaneously extending the duration of hemodynamically stable ex vivo uterine environment therapy to 1 week.Merino-cross ewes with timed, singleton pregnancies were surgically delivered at 112-115 days of gestation (term is ∼150 days) and adapted to ex vivo uterine environment therapy (treatment group; n = 6). Physiological variables were continuously monitored; humerus and femur length, ductus arteriosus directional flow, and patency were estimated with ultrasound; serial blood samples were collected for hematology and microbiology studies; weight was recorded at the end of the experiment. Control group animals (n = 7) were euthanized at 122 days of gestation and analyzed accordingly. Bacteremia was defined by positive blood culture. Infection and fetal inflammation was assessed with white blood cell counts (including differential leukocyte counts), plasma and lung proinflammatory cytokine measurements, and lung histopathology.Five of 6 fetuses in the treatment group completed the 1-week study period with key physiological parameters, blood counts remaining within normal ranges, and no bacteremia detected. There were no significant differences (P.05) in arterial blood oxygen content or lactate levels between ex vivo uterine environment therapy and control groups at delivery. There was no significant difference (P .05) in birthweight between control and ex vivo uterine environment groups. In the ex vivo uterine environment group, we observed growth of fetal humerus (P.05) and femur (P.001) over the course of the 7-day experimental period. There was no difference in airway or airspace morphology or consolidation between control and ex vivo uterine environment animals, and there was no increase in the number of lung cells staining positive for T-cell marker CD3Five preterm lambs were maintained in a physiologically stable condition for 1 week with significant growth and without clinically significant bacteremia or systemic inflammation. Although substantial further refinement is required, a life support platform based around ex vivo uterine environment therapy may provide an avenue to improve outcomes for extremely preterm infants.

Introduction Ex-vivo uterine environment (EVE) therapy uses an artificial placenta to provide gas exchange and nutrient delivery to a fetus submerged in an amniotic fluid bath. Development of EVE may allow us to treat very premature neonates without mechanical ventilation. Meanwhile, elevations in fetal inflammation are associated with adverse neonatal outcomes. In the present study, we analysed fetal survival, inflammation and pulmonary maturation in preterm lambs maintained on EVE therapy using a parallelised umbilical circuit system with a low priming volume. Methods Ewes underwent surgical delivery at 115 days of gestation (term is 150 days), and fetuses were transferred to EVE therapy (EVE group; n = 5). Physiological parameters were continuously monitored; fetal blood samples were intermittently obtained to assess wellbeing and targeted to reference range values for 2 days. Age-matched animals (Control group; n = 6) were surgically delivered at 117 days of gestation. Fetal blood and tissue samples were analysed and compared between the two groups. Results Fetal survival time in the EVE group was 27.0 ± 15.5 (group mean ± SD) hours. Only one fetus completed the pre-determined study period with optimal physiological parameters, while the other 4 animals demonstrated physiological deterioration or death prior to the pre-determined study end point. Significant elevations (p0.05) in surfactant protein mRNA expression level between the two groups. Conclusion In this study, we achieved limited fetal survival using EVE therapy. Despite this, EVE therapy only induced a modest fetal inflammatory response and did not promote lung maturation. These data provide additional insight into markers of treatment efficacy for the assessment of future studies.

Background:Single fetal death (sFD) in monochorionic twin pregnancies is associated with substantial morbidity and mortality in the survivor. The aim of our study was to evaluate the rate of cerebral lesions detected at fetal Magnetic Resonance Imaging (MRI) and to correlate the results with the neurologic outcome of the survivors of monochorionic twin pregnancies after sFD.Methods:Between 2005 and 2012, 11 monochorionic twin pregnancies with sFD and subsequent fetal MRI of the survivor were included. All neonates underwent neurologic assessment after birth and 56% of surviving infants underwent long-term neurologic assessment. MRI findings and neurologic outcome of the survivors were evaluated.Results:Gestational age at sFD was 20.9 (±2.9) weeks; 55% (6/11) of survivors of monochorionic twin pregnancies after sFD showed cerebral lesions at fetal MRI; 72% (8/11) of all survivors had normal neonatal neurologic outcome: all survivors with normal fetal MRI and 50% of survivors with cerebral lesions at fetal MRI. Long-term neurologic assessment was normal in all tested patients with normal fetal MRI and in one of three tested patients with cerebral lesions at fetal MRI.Conclusion:Survivors of monochorionic twin pregnancies after sFD show a high rate of cerebral lesions at fetal MRI. The importance of cerebral lesions at fetal MRI in survivors after sFD in monochorionic twin pregnancies is uncertain. All tested survivors with normal fetal MRI showed normal neurologic outcome but only one of three survivors with cerebral lesions at fetal MRI showed normal long-term neurologic outcome.